Human immunodeficiency virus (HIV) is recognized as the causative agent in AIDS.
Current therapies for HIV infection focus on inhibiting the activity of viral enzymes which are essential to the life cycle of the virus. The agents that are presently in use fall mainly into three classes, designated Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs), and Protease Inhibitors (PIs). Presently, combination therapies, i.e. the selection of two or more antiretroviral agents taken together to make up a “drug cocktail,” are the preferred treatment for HIV infection. Combination therapies have been shown to reduce the incidence of opportunistic infections and to increase survival time. Typically, the drug cocktail combines drugs from different classes, so as to attack the virus at several stages in the replication process. This approach has been shown to reduce the likelihood of the development of virus forms that are resistant to a given drug or class of drugs.
Treatment failure with rebound of the amount of HIV which can be measured in the blood is common for patients treated with combination antiretroviral regimens. Resistance to the drugs in the drug regimen develops as the virus replicates in the presence of these drugs. Because of structural similarities of the drugs within an antiretroviral class, cross resistance is commonly seen to the other members of that class (for example virologic failure on a regimen containing an NNRTI will lead to cross resistance to the other first generation NNRTI agents). As patients experience repeated virologic failure on antiretroviral combination therapy, their viruses develop broad multi-class antiretroviral drug resistance which limits the effectiveness of the next round of antiretroviral therapy. Many highly treatment experienced patients have been exposed to all three classes of antiretroviral drugs and cannot obtain two active drugs to form the core of a new, effective antiretroviral drug regimen.
Tipranavir is a known agent for the treatment of HIV infection.
Tipranavir, also known as U-140690 and PNU-140690, is an HIV protease inhibitor. Chemically, tipranavir is (6R)-3-((1R)-1-[3-({[5-trifluoromethyl)(2-pyridyl)]sulfonyl}amino)phenyl]propyl}-4-hydroxy-6-(2-phenylethyl)-6-propyl-5,6-dihydro-2H-pyran-2-one or ([R-(R*,R*)]-N-[3-[1-[5,6-dihydro-4-hydroxy-2-oxo-6-(2-phenylethyl)-6-prop yl-2H-pyran-3-yl]propyl]phenyl]-5-(trifluoromethyl)-2-pyridinesulfonamide) and has the following structural formula:

Tipranavir and methods for its synthesis and use in the treatment of HIV are described in WO 95/30670 and corresponding U.S. Pat. No. 5,852,195. Pharmaceutical formulations suitable for the oral administration of tipranavir are described in WO 99/06043 and WO 99/06044, and the corresponding U.S. Pat. Nos. 6,121,313 and 6,231,887.
As tipranavir is metabolized relatively rapidly by the cytochromes P450, especially the Cyp3A4 isoform, it is preferred to co-administer an inhibitor of Cyp3A4 in order to obtain therapeutically effective blood levels of tipranavir. The use of ritonavir for this purpose is described in U.S. Pat. No. 6,147,095. The use for this purpose of other inhibitors of Cyp3A4 is also possible.
Furthermore Compounds of the Formula (I)
wherein Base is selected from the group consisting of thymine, cytosine, adenine, guanine, inosine, uracil, 5-ethyluracil and 2,6-diaminopurine, or a pharmaceutically acceptable salt or prodrug thereof, are described in the WO 88/00050 and WO 91/01137 for the therapeutic and prophylactic control and treatment of AIDS, HIV infections, hepatitis B virus (HBV) infections and retrovirus infections in animals and man. These nucleoside compounds are transformed by cells or enzymes to triphosphates which inhibit the reverse transcriptase of retrovirus as well as the activity of DNA dependent polymerase of hepatitis B virus.
Combinations of tipranavir with at least one compound of the formula (I) which exhibit potent therapeutic activity against HIV and HBV would greatly aid in the development of new combination therapy against human retroviral (HRV) infections and HBV.